Nerves in mature mammals, such as the optic nerve, do not normally regenerate after injury. Retinal ganglion cells (RGCs) initiate a sprouting reaction at their damaged nerve endings, but this growth is abortive and the cells soon begin to die (Ramon y Cajal, 1991). Nonetheless, RGCs can regenerate lengthy axons through a peripheral nerve graft (Aguayo et al., 1991) and even through the optic nerve itself if the lens is injured (Fischer et al., 2000; Leon et al., 2000), or if a fragment of peripheral nerve is implanted into the vitreous (Berry et al., 1996). These latter manipulations lead to the appearance of activated macrophages in the eye, and it has been recently shown that intravitreal macrophage activation is sufficient to allow RGCs to regenerate their axons through the optic nerve (Leon et al., 2000; Yin et al., 2003). In culture, a macrophage-derived protein, acting in concert with a small molecule that is constitutively present in the vitreous, stimulates mature rat RGCs to regenerate their axons in a cAMP-dependent fashion (Yin et al., 2003).
In contrast to mammals, fish and amphibia can regenerate their optic nerves throughout life (Jacobson, 1991). In culture, the most potent axon-promoting factor for goldfish RGCs is a small hydrophilic molecule (<500 Daltons) that is secreted by non-neuronal cells of the optic nerve. This molecule is referred to as AF-1 (Schwalb et al., 1995; Schwalb et al., 1996).
Understanding the factors involved in mammalian and non-mammalian neuron regeneration will aid in the development of potential therapeutics for treatment of neuronal disorders. Disorders of the peripheral and central nervous system are widespread, and for many of these conditions effective therapeutic interventions are lacking. Neurological disorders may be caused by an injury to a neuron, such as a mechanical injury or an injury due to a toxic compound, by the abnormal growth or development of a neuron, or by the misregulation (such as downregulation or upregulation) of an activity of a neuron. There is a need in the art for methods and compositions that can improve the ability of a neuron, or portion of the nervous system, to resist insult, to regenerate, and to maintain desirable function, which can be used for treatment of neurological disorders.